Human immunodeficiency viruses (HIVs) may comprise a spectrum of human retroviruses with varying potential for latency, virulence and pathogenicity. These capacities may be governed, in part, by their genetic structure. This project aims to gain an understanding of pathogenicity by analyzing the structure and function of the genomes of the highly pathogenic (HIV-2[ROD]) and weakly pathogenic (HIV-2[ST]) HIVS. Since much of the virus regulation is centered in its long terminal repeat (LTR), relevant to latency and virulence, and the envelope gene plays a major role in pathogenicity, the focus of this study is the LTR-based regulatory elements and regulatory genes (tat), and the envelope gene. Also relevant are the properties of these viruses to be activated by cofactors, e.g., T cell activation. We recently presented the novel observation of two enhancer elements in HIV-2 that regulate virus expression. Apparently, the activation of HIV-2 with the second enhancer as the target does not involve the NFkappaB pathway followed for HIV-1 activation. The presence of two enhancers in HIV2 raises the possibility that these enhancers may function differentially depending on the cell phenotype and environmental factors and this may underline virus latency. In addition to the previously known regulatory elements, our studies show that HIV-2 contains sequence elements downstream of the transcriptional initiation site that have repressive effect on gene expression. Studies mapping the functional domains of HIV-2 TAT suggest that the amino terminus region of the TAT protein may be important for its function and specificity. In an attempt to map determinants of fusogenicity and pathogenicity of HIV, analysis of the chimeric proviruses between noncytopathic HIV-2(ST) and cytopathic HIV-2(ROD) revealed that the env gene is a major determinant of cytopathicity and presumably pathogenicity. Apparently, fusogenicity and cytopathogenicity determinants encompass multiple and discontinuous epitopes, and their ability to cause cytopathic effects may be coupled with the capacity to replicate and this may be cell-type dependent.